The cancer/testis antigens represent promising targets for the development of new therapies against melanoma.

Melanoma treatment has evolved substantially over recent decades, incorporating targeted therapies and immunotherapy alongside conventional approaches such as surgery, chemotherapy, and radiotherapy. Despite these advances, achieving high tumor specificity while minimizing off-target toxicity remains a major clinical challenge. In this context, Cancer-Testis Antigens (CTAs) have emerged as highly promising immunotherapeutic targets due to their predominant expression in malignant cells, strong immunogenicity, and functional involvement in tumor progression and survival. Therefore, this review aims to critically analyze the immunogenic and oncogenic potential of CTAs, synthesize current preclinical and clinical evidence across distinct CTA subfamilies, and highlight innovative CTA-based immunotherapeutic strategies for the treatment of melanoma. Increasing evidence indicates that CTAs play critical roles in maintaining tumor cell viability, genomic stability, and immune evasion, thereby offering unique opportunities for the development of highly specific anticancer therapies. Preclinical and clinical studies evaluating vaccines based on single or multiple CTAs, in combination with chemotherapeutic agents, adoptive T-cell therapies, and immune checkpoint inhibitors have demonstrated encouraging outcomes, particularly involving MAGE (melanoma-associated antigen), New York esophageal squamous cell carcinoma 1 (NY-ESO-1), and preferentially expressed antigen in melanoma (PRAME). Nevertheless, several biological and translational challenges remain. In this scenario, the future success of CTA-based therapies will depend on a deeper understanding of their molecular mechanisms, intratumoral expression heterogeneity, and immunological interactions, as well as on the rational design of combinatorial and personalized therapeutic approaches.